Previous studies have shown that patients with rapid-cycling manic depressive illness are more likely to develop lithium induced hypothyroidism and goiter than patients with less frequent relapses. These patients also develop elevated thyroid stimulating hormone levels (TSH) in the presence of normal thyroid indices when they are treated with lithium. Previous open clinical trials suggest that the mood disorder of rapid cycling patients may improve with hypermetabolic doses of thyroxine but as yet controlled clinical trials are lacking. Previous controlled trials of thyroxine were not effective in non-rapid cycling depressed patients suggesting that the abnormalities in thyroid function and a clinical response to thyroxine are defining characteristics of the rapid-cycling bipolar population. As part of a continuing study, we are further delineating the nature and etiology of the hypothalamic-pituitary thyroid dysregulation in rapid cycling patients. Studies include circadian profiles of TSH drawn every 30 minutes, morning and evening TRH stimulated TSH responses, and determination of the pituitary set point to thyroxine. Together these studies should enable us to determine whether the abnormalities of thyroid regulation seen in these patients arise from changes at the level of the hypothalamus, the pituitary gland or the thyroid gland. Following these evaluations patients undergo a double-blind controlled trial of euthyroid and hypermetabolic dose of thyroxine for the treatment of their affective disorder. In addition to clinical measures, this study will enable us to assess the important interactions between thyroxines, norepinephrine, and mood, as measured by changes in the whole body norepinephrine turnover during the course of treatment.